BACKGROUND: Overexpression of the Receptor for Advanced Glycation End-product (RAGE) has been associated with chronic inflammation, which in turn has been associated with increased colorectal cancer (CRC) risk. Soluble RAGE (sRAGE) competes with RAGE to bind its ligands, thus potentially preventing RAGE-induced inflammation.

METHODS: To investigate whether sRAGE and related genetic variants are associated with CRC risk, we conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma sRAGE concentrations were measured by ELISA in 1,361 CRC matched case-control sets. Twenty-four single nucleotide polymorphisms (SNPs) encoded in the genes associated with sRAGE concentrations were available for 1,985 CRC cases and 2,220 controls. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional and unconditional logistic regression for CRC risk and circulating sRAGE and SNPs, respectively.

RESULTS: Higher sRAGE concentrations were inversely associated with CRC (ORQ5vs.Q1=0.77, 95%CI=0.59-1.00). Sex-specific analyses revealed that the observed inverse risk association was restricted to men (ORQ5vs.Q1=0.63, 95%CI=0.42-0.94) whereas no association was observed in women (ORQ5vs.Q1=1.00, 95%CI=0.68-1.48, Pheterogeneity for sex=0.006). Participants carrying minor allele of rs653765 (promoter region of ADAM10) had lower CRC risk (C vs. T, OR=0.90; 95%CI=0.82-0.99).

CONCLUSIONS: Pre-diagnostic sRAGE concentrations were inversely associated with CRC risk in men but not in women. A SNP located within ADAM10 gene pertaining to RAGE shedding, was associated with CRC risk.

IMPACT: Further studies are needed to confirm our observed sex difference in the association and better explore the potential involvement of genetic variants of sRAGE in CRC development.